Helicobacter pylori (H. pylori) is a highly motile, S-shaped, microaerophilic gram-negative bacterium that colonizes in the stomach. H. pylori infection is widespread with seroprevalence in the developed world between 30-60%. Infection with the bacterium is usually contracted during childhood and patients remain infected for life unless treated. H. pylori infection has been shown to result in the development of gastritis, peptic ulcer, and mucosa-associated lymphoid tissue (MALT) lymphoma and has been linked to gastric adenocarcinoma (Go, M. F. and D. T. Smoot, Helicobacter pylori, gastric MALT lymphoma, and adenocarcinoma of the stomach Seminars in Gastrointestinal Disease, 2000, 11(3): p. 134-141). Eradication of H. pylori infection is currently achieved using combination therapy of antimicrobial and antisecretory agents (Malfertheiner, P., A. Leodolter, and U. Peitz, Cure of Helicobacter pylori-associated ulcer disease through eradication Bailliere's Best Practice and Research in Clinical Gastroenterology, 2000, 14(1): p. 119-132). However, compliance to these therapies is compromised due to adverse side effects and cumbersome dosing regimens. In addition, increasing prevalence of H. pylori strains resistant to existing antimicrobial therapies threatens to limit the use of these treatments (Qureshi, W. A. and D. Y. Graham, Antibiotic-resistant H. pylori infection and its treatment. Current Pharmaceutical Design, 2000, 6(15): p. 1537-1544). Given these considerations, a therapy for H. pylori infection would be a novel antimicrobial monotherapy that is selective for H. pylori eradication. The selectivity attribute is expected to aid in minimizing side effects on gut flora.
H. pylori, like all Gram positive and Gram negative bacteria, utilize a cell wall comprised of crosslinked peptidoglycan units to maintain shape and resist high osmotic pressure potentials. Bacterial cell wall biosynthesis is a validated target for antimicrobial activity; cephalosphorins, penicillins and glycopeptides are antimicrobial agents, which block cell wall biosynthesis (Walsh, C., Molecular mechanisms that confer antibacterial resistance. Nature, 2000, 406: p. 775-781). Cell wall biosynthesis requires the enzyme MurI, a glutamate racemase, and therefore this enzyme is essential for bacterial viability (Doublet, P., et al., The murI gene of Escherichia coli is an essential gene that encodes a glutamate racemase activity. Journal of Bacteriology, 1993, 175(10): p. 2970-9).
The present invention describes compounds, which specifically inhibit H. pylori MurI, compositions of such compounds and methods of use. The compounds disclosed herein represent a valuable contribution to the development of selective therapies directed to diseases resulting from H. pylori infection.